The goal of this proposed work is to characterize the function of the histone demethylase, LSD1, in the DNA damage response (DDR). LSD1 has been shown to regulate many genes and act in a number of distinct biological and pathological pathways, particularly in cancer. Small molecule inhibitors of LSD1 have begun to be characterized in preclinical studies;indeed, these show promise as a novel modality for epigenetic therapy for a number of different types of cancer. However, the function of LSD1 in the DDR pathway and its role in genomic stability is just beginning to be uncovered. Preliminary results, using a combination of biochemistry, molecular biology and cell biology, reveal that LSD1 functions in the DDR pathway upstream of the 53BP1 tumor suppressor. These results demonstrate that LSD1 performs this function by regulation of ubiquitylation at sites of DNA damage. The hypothesis that LSD1 functions directly in this pathway and is a critical component of the DDR machinery will be tested by a number of biochemical and molecular strategies. The work proposed here will be conducted under the mentorship of Dr. Yang Shi, discoverer of LSD1 and a world leader in chromatin research. The candidate is an M.D., Ph.D. with training in clinical pathology and seeks further training in basic research. The long-term goal is to establish and direct an independent research laboratory studying the role of chromatin in genomic maintenance. It is anticipated that the project will yield important insight into the mechanisms of genomic stability and will prepare the candidate for a career as an independent investigator. PUBLIC HEALTH RELEVANCE: The research proposed in this grant has significance for the way in which cells guard their genome, a pathway important for cancer development. The proposed studies will shed light on the molecular mechanisms in this pathway, and may lead to novel diagnostic and therapeutic avenues in cancer.